Neuropathic pain is a chronic condition resulting from damage to sensory nerves in the peripheral nervous system. Common examples of neuropathic pain include injury incurred from stroke and spinal cord injury, phantom limb and causalgia (burning pain) post-nerve damage; primary symptoms include allodynia (sensitivity to stimuli which does not normally evoke pain), hyperalgesia (increased sensitivity to noxious stimuli), paresthesia (tingling sensations), spontaneous nociceptor discharge (ectopic discharge), as well as spontaneous pain. Current clinical treatments for neuropathic pain include synthetic opioids, non-steroidal inflammatory drugs (NSAIDS), and anticonvulsants. However the use of these can be troublesome as tolerance, abuse, and dependence often result from their use. One such tolerance mechanism being studied is the splicing of the mu opioid receptor (μ)—the primary target of common synthetic opioid analgesics morphine, fentanyl, and methadone—which can undergo subunit rearrangement through alternative splicing, producing various receptor variants with differing affinities for these synthetic opioids.
The human body's natural mechanism for analgesia involves the endogenous opioid neuropeptides, composed of three classes: the enkephalins, endorphins, and dynorphins, which are proteolytic fragments of proenkephalin, proopiomelanocortin (POMC), and prodynorphin, respectively. The opioid neuropeptides are characterized by their affinity for the 3 opioid receptors (μ, δ, κ) present in the central and peripheral nervous system, and by the reversal or block of analgesia by the synthetic opioid antagonist naloxone. The opioid receptors are members of the G-protein coupled receptor (GPCR) class of membrane proteins—composed of 7 transmembrane spanning segments coupled to an inhibitory G protein (Gα1), and implicated in various behavioral effects including analgesia, reward, depression, anxiety, and addiction. The endogenous opioid neuropeptides work by binding their cognate GPCR partner, which is coupled to an inhibitory G protein (Gα1), eventually leading to the inhibition of N-type Ca2+ channels and excitatory neurotransmitter release. Peripheral pain signals are transmitted through afferent nerve fibers into the dorsal root ganglion by way of the spinal cord, and up towards the brain. The action potentials stimulated across these afferent nerve fibers propagate along the central nervous system, triggering the opening of N-type Ca2+ channels and the release of excitatory neurotransmitters (Glu, CGRP, substance P)—which activate postsynaptic receptors on upstream neurons, all cooperating to transmit the pain signal. The inhibition of these signals, stimulated by the binding and actions of the endogenous opioids, is one of the body's homeostatic mechanisms to counteract pain.
Opioids are a large class of drugs, used clinically as painkillers that include both plant-derived and synthetic alkaloids and peptides found endogenously in the mammalian brain. While the plant-derived alkaloids have been known and used for thousands of years, the endogenous opioid peptides were discovered only in the mid-1970s. These are known to comprise three distinct gene families: β-endorphin and other peptides derived from proopiomelanocortin; enkephalins, derived from proenkephalin A; and the dynorphins, derived from proenkephalin B.
Opioid compounds interact with neuronal cells and modulate physiological functions such as nociception. Thus, one of the physiological effects attributed to the opioid system is analgesia.
Endogenous opioids exist in multiple forms in the central nervous system, and include the dynorphins, which are a series of peptides derived from the precursor prodynorphin (proenkephalin B). The first of the dynorphins to be isolated was the 17 amino acid peptide having the structure shown (and designated SEQ ID NO:1), sometimes also referred to as “dynorphin A-(1-17)”:
(SEQ ID NO: 1)Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu- Lys-Trp-Asp-Asn-Gln
Within the last decade, various U.S. patents have described and suggested uses of dynorphin.
U.S. Pat. No. 4,396,606, issued Aug. 2, 1983, describes isolation of a compound (sometimes hereinafter called “dynorphin A-(1-13)”) with the structure:
(SEQ ID NO: 2)Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-LysThis fragment of the seventeen amino acid endogenous peptide was found to be substantially more active than the enkephalins and β-endorphin in a guinea pig ileum test. Compositions containing dynorphin were suggested to be analgesic by virtue of their interaction with opioid receptor sites, and administration in the same manner as other opioid agonists (e.g. morphine) was disclosed.
U.S. Pat. No. 4,462,941, issued Jul. 31, 1984, describes dynorphin amide analogs with ten amino acid residues. These dynorphin A-(1-10) amide analogs do not have significant analgesic activity in opioid tail flick tests (unless given in huge doses where they tend to produce convulsions).
Enkephalin analogues that are conformationally constrained by a cyclic structure (such as with a disulfide bridge) are described by U.S. Pat. No. 4,518,711, issued May 21, 1985. Subsequently, dynorphin analogues have become known that have cysteine replacements at the amino acid residue 5 (usually leucine) and at the amino acid residue 11 (usually lysine). The amino acid residue 8 (usually an isoleucine) and the amino acid residue 13 (usually a lysine) have similarly been replaced by cysteines in a bridged relationship. The bridges, or cyclic structures, appear to assist in stabilizing the dynorphin analogues against in vivo degradations.
Lee et al., International Publication No. WO93/25217, discloses therapeutic uses of certain truncated N-terminal dynorphin A analogues in conjunction with narcotic analgesics in order to potentiate activity of the narcotic analgesic and/or to block withdrawal symptoms. However, uses in conjunction with narcotic analgesics for opioid effects require a presence of opioid drugs.
Opioid drugs are used clinically as painkillers, but their usefulness is limited by the tolerance and dependence that normally develops upon chronic treatment. Tolerance may be defined as an increase in the amount of drug needed to achieve a certain level of analgesia, while dependence manifests itself in the need to continue taking drug to prevent withdrawal symptoms. Despite a great deal of research on these phenomena, little is known about their molecular basis. Opioid drugs, such as, for example, morphine, are addictive and have central opioid side effects such as drowsiness and impairment of mental activity.
Some non-opiate compositions have been suggested for relieving chronic pain, such as experienced as burning or hyperesthesia pain. Thus, U.S. Pat. No. 5,006,510, issued Apr. 9, 1991, describes somatostatin analogue compositions for topical administration in the treatment of pain where opiates do not significantly change the experience of the patient's pain.
Nevertheless, a variety of painful conditions exist that are relatively resistant to analgesic relief by narcotic analgesics such as morphine.
The foregoing discussion of the prior art derives primarily from PCT Published Application WO/96/06626 which describes the use of certain peptides, more specifically, certain analogs of dynorphin A that are truncated, with respect to endogenous dynorphin at the N-terminus for inducing analgesia in a patient experiencing chronic pain. According to the inventors, administration of these particular peptides provides non-opiod analgesia whereby the central nervous system side effects of a drug such as morphine, e.g. drowsiness, impaired mental functioning and the like, are avoided.